AbstractMesotheriidae (Panperissodactyla, Notoungulata) are an extinct clade (early Oligocene–Pleistocene) of small to medium‐sized herbivorous mammals that were widely distributed in South America. Although two subfamilies traditionally have been recognized (Trachytheriinae and Mesotheriinae), recent cladistic analyses based on discrete characters have indicated that “Trachytheriinae” is a paraphyletic assemblage. Given the availability of a large number of specimens and the fact that dental characters are the most common characters used in mesotheriid phylogenies, we performed specimen‐level cladistic analyses combining discrete, continuous and geometric morphometrics‐based dental characters. The aim was to: (1) include new scored morphological characters to solve the phylogenetic relationships of Mesotheriidae; (2) compare the results of the upper and lower dentition analyses as different character partitions and in combination, to establish phylogenetic hypotheses; and (3) trace the evolution of dental traits. Phylogenetic analyses employing characters of associated upper and lower dentitions recovered one most parsimonious tree with Archaeohyracidae (outgroup) as the sister group of Pan‐Mesotheriidae (= Mesotheriidae; converted clade name), this latter composed of trachytheriines (stem‐mesotheriine) + Mesotheriinae (converted clade name). Within Mesotheriinae, we recovered two main lineages phylogenetically defined here as Bolivarini and Pampaini (new clade names). Analyses of isolated upper and lower dentition sub‐datasets each resulted in one most parsimonious tree congruent with the associated dentition. Our study emphasizes the use of geometric morphometrics characters to resolve additional clades in phylogenetic analyses, provides information on the evolution of size and morphology of teeth, and exposes specimen assignment issues at a taxonomic level. The integration of osteological characters might be crucial to further understanding the evolution of Mesotheriidae.